3-(Chlorocetamido)-5-methyl isoxazole

ABSTRACT

A novel process for preparing 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (I), starting with 3-amino-5-methylisoxazole (II) is disclosed. Compound I exhibits anti-inflammatory properties and is useful for treating inflammation. In the process of the invention an intermediate obtained, 2,3-dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide 1,1-dioxide (IV) undergoes rearrangement to provide 1-{[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanone S,S-dioxide (V), which is methylated, according to conventional procedures. The methylated intermediates VI, upon further treatment, undergoes a second rearrangement to obtain the desired anti-inflammatory compound I.

This is a division of application Ser. No. 577,568 filed May 21, 1975.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is concerned with a process for the production of4-hydroxy-3-(5-methyl-3-isoxazolyl-carbamoyl)-2-methyl-2H-1,2-benzothiazine1,1-dioxide (IV) and to certain intermediates used in the productionthereof.

2. Description of the Prior Art

As disclosed by Zinnes, Schwartz and Shavel, in U.S. Pat. No. 3,822,258,4-hydroxy-3-(3-isoxazolylcarbamoyl)-2H-1,2-benzothiazine 1,1-dioxidesexhibit anti-inflammatory activity. According to U.S. Pat. No.3,822,258, these active compounds are prepared by reacting a2-substituted-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxidewith a substituted 3-aminoisoxazole. Other synthetic routes forobtaining4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine1,1-dioxide have been disclosed by Lombardino in U.S. Pat. No. 3,853,862and by Sircar, Zinnes and Shavel in U.S. Pat. No. 3,821,211. A keyintermediate in the Lombardino process inN-aryl-N'-alkyl-N'-(2'-alkyoxycarbanoyl-benzenesulfonyl)-glycineamide.The Sircar et al. process describes the treatment of a pyrrolidineenamine of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-dioxidewith phosgene and triethylamine, followed by the reaction of thecompound obtained with 3-amino-5-methylisoxazole, and hydrolysis.

Related anti-inflammatory agents and processes for their preparation aredescribed by Lombardino in U.S. Pat. No. 3,591,584 and by Rasmussen inU.S. Pat. No. 3,501,466. Lombardino et al., in J. Med. Chem. 14:1171-1175 (1971) shows the preparation of3-methoxycarbonyl-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide from3-oxo-1,2-benzisothiazoline-2-acetic acid methyl ester. Zinnes et al.discuss a similar reaction starting with the analogous methyl ketone inJ. Org. Chem. 30: 2241-2246 (1965).

Rearrangement reactions of substituted isoxazoles and oxadiazoles arediscussed generally in H. C. Van Der Plas, Ring Transformations ofHeterocycles, Volume 1, Chapter 3, 1973, Academic Press, London, NewYork.

SUMMARY OF THE INVENTION

A process for the production of the compound of the formula: ##SPC1##

is described. 3-Amino-5-methylisoxazole (II) is reacted with ahaloacetylhalide to obtain 3-(haloacetamido)-5-methylisoxazole (III)which is then reacted with an alkali metal salt of saccharin to formcompound IV: ##SPC2##

Compound IV is treated with an alkali metal alkoxide in an inert solventat a controlled temperature to form the benzothiazine-oxadiazolederivative V: ##SPC3##

which is methylated on the sulfonamide nitrogen by conventionalprocedures, at controlled temperatures, to yield the correspondingmethylated compound VI. Compound VI is then transformed into the desiredcompound I by heating with a base. Alternatively, compound V may berearranged and methylated in a one-step reaction by heating with amethylating agent in a solvent/base system.

DESCRIPTION OF THE PARTICULAR EMBODIMENTS

According to the present invention, a novel process for the productionof4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine,1,1-dioxide (I): ##SPC4##

is initiated by reacting compound II: ##SPC5##

with haloacetylhalide, such as chloroacetylchloride in an inert solvent,such as chloroform, containing excess organic base, preferably pyridine.After stirring the reaction mixture for several hours, compound III isobtained: ##SPC6##

which is then condensed with an alkali metal salt of saccharin,preferably sodium saccharin, in an inert solvent, such asN,N'-dimethylformamide (DMF). Reactants are used in approximatelyequimolar quantities and the condensation reaction may be conducted forexample, at about 100°C. for about three hours, to yield compound IV:##SPC7##

Rearrangement of IV is effected using an alkali metal alkoxide of alower alcohol, such as sodium methoxide, in an inert solvent at acontrolled temperature. Typically, more than three moles, preferablyabout four moles of sodium methoxide per mole of IV in dimethylformamideat a preferred temperature of from about 60°C. to about 70°C. is usedfor the rearrangement. After acidification with a mineral acid, forexample HCl, compound V is obtained: ##SPC8##

The success of this dual rearrangement is dependent on the reactiontemperature, since lower or higher temperatures have been found to yieldunsatisfactory results.

Conversion of V to compound VI is effected by conventional methylationprocedures using standard methylating agents such as methyl iodideand/or dimethylsulfate in aqueous inert solvents such as the loweralcohols, containing excess base. The reaction temperature is controlledpreferably, between 10°C.-25°C., as higher temperatures do not affordcompound VI, as is more fully exemplified below. Typically, an excess,preferably two equivalents of aqueous sodium hydroxide are employed withProprietary Solvent No. III (SOLOX) with an excess, preferably 1.5equivalents of dimethylsulfate. SOLOX, which is sold commercially byU.S. Industrial Chemical Co., New York, N.Y., is a general-purposesolvent formulation comprised of specially denatured alcohol with lowpercentages of solvent modifiers. Stirring the above reaction mixturefor about 3 hours, at temperatures ranging between about 10°C. to 25°C.,afforded, after acidification with a mineral acid, compound VI: ##SPC9##

Transformation of VI to the title compound I is effected by heating (>100°C.) in an inert solvent, such as xylene, containing an organic base,preferably triethylamine. Heating VI (90°C.-100°C.) in an aqueous basesuch as sodium hydroxide also affords I after acidification.

Alternatively, compound V may be converted to compound I usingconventional methylating agents in aqueous alcohols containing an excessof base at elevated temperatures. For example, compound V is placed inSOLOX containing an excess, preferably 3.5 equivalents of aqueous sodiumhydroxide, with an excess, preferably 1.5 equivalents ofdimethylsulfate, and heated at reflux (about 75°C. to 80°C.) for aboutone and one half hours. After acidification, compound I is obtained.

Direct conversion of compound V to compound I is also effected in anon-aqueous medium, such as dimethylformamide, at elevated temperatures(about 50°C. to 80°C., preferably 60°C.), using an excess, preferablytwo equivalents of a metal hydride base, preferably sodium hydride,followed by the addition of a conventional methylating agent, such asmethyl iodide. Acidification affords compound I.

The corresponding alkali metal, alkaline earth metal and amine salts offinal compound I may be prepared by treating compound I with the desiredbase, e.g., sodium alkoxide, potassium alkoxide, sodium hydroxide,potassium hydroxide, calcium hydroxide, pyrrolidine and the likeaccording to conventional procedures. If desired, the alkali metal saltof compound I may be obtained directly in certain of the procedures ofthis invention by omission of the acidification reaction in the finalprocess step.

The starting material 2-amino-5-methylisoxazole (II) used in the processof this invention is known and may be prepared as described inNetherlands Pat. No. 6,511,924. Compound II is commercially availablefrom Hoffmann La Roche, Nutley, New Jersey.

The final compound (I) prepared according to the process of thisinvention, is described in U.S. Pat. No. 3,816,828, as having usefulanti-inflammatory, anti-pyretic and analgesic properties. Whenadministered orally to rats at a dose of 10-200 mg/kg, it is able tocause reduction in swelling of the paw induced by injection into thefoot pads of an irritant such carrageenin. Therapeutically orprophylactically administered orally at a dose of 15-200 mg/kg, thecompound inhibits adjuvant induced polyarthritis in the rat. Oral dosesof 25-100 mg/kg are sufficient to inhibit yeast induced hyperthermia inthe rat. At oral doses of 25-200 mg/kg it exhibits a significantanalgesic effect as determined by the phenylquinone writhing procedurein mice.

Generally speaking, compound I is indicated in conditions such as painresulting from arthritis, bursitis, and the like. A daily dosage regimenof about 0.5 grams to about 2 grams in several divided doses isrecommended for a mammal weight about 70 kg body weight to relieve thepain and swelling associated with these conditions. Compound IV may beadministered either orally or by injection.

In order to use compound I, it is formulated into dosage forms such astablets or syrups by blending with an inert pharmaceutical carrier suchas lactose or simple syrup by methods well known to the pharmacists art.For injectionable dosage forms, it is formulated with vehicles such aswater, peanut oil, sesame oil, and the like. In these dosage forms, theactive ingredient is from about 0.5 grams to 1 grams per dosage unit.

The following definitions apply to all of the compounds and reactionprocedures of this invention, as well as to reagents and intermediatesused in the preparation thereof: halogen is meant to include chlorine,bromine an iodine; the term alkali metal is meant to include sodium,potassium and the like; the term lower alcohol is meant to include 1 to5 carbon, straight or branched chain alcohols; the term base is meant toinclude those bases commonly used in an aqueous reaction medium, such assodium hydroxide, potassium hydroxide and the like; the term organicbase is meant to include those bases commonly used in a non-aqueousreaction medium, such as pyridine, diethylamine, triethylamine, and thelike; the term metal hydride base is meant to include alkali metal andalkaline earth metal hydrides such as sodium hydride, potassium hydride,calcium hydride and the like.

In order to further illustrate this invention, the following examplesare provided:

EXAMPLE 1 ##SPC10## 3-(Chloroacetamido)-5-Methylisoxazole

To 800 ml of chloroform is added 118 grams (1.12 moles) of3-amino-5-methylisoxazole followed by 118 grams (1.5 moles) of pyridine.To this solution is added 147 grams (1.3 moles) of chloroacetylchloridewith the addition temperature maintained at 0°-10°C. The reaction isthen stirred at room temperature for 1 hour, filtered and dried in avaccum desiccator to give 116 grams (56%) of3-(chloroacetamido)-5-methylisoxazole, mp 192°-195°C. This material isslightly irritating to the skin and due caution should be exercised.

Analysis: Calc'd for C₆ H₇ ClN₂ O₂ (174.58): C, 41.28; H, 4.04; N,16.05; Cl, 20.31. Found: C, 41.55; H, 4.10; N, 15.79; Cl, 20.50.

EXAMPLE 2 ##SPC11##

To 2.31 liters of DMF is added 479 grams (2.75 moles) of3-(chloroacetamino)-5-methylisoxazole followed by 699 grams (2.9 moles)of sodium saccharin dihydrate. The mixture is heated to 100°C. and thistemperature is maintained for 2 hours. The cooled reaction mixture ispoured into 8 liters of water, filtered and the wet cake isrecrystallized from 15 liters of ethanol to give 658 grams (74.8%) of2,3,dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide1,1-dioxide, mp 218°-220°C.; I.R. and NMR spectra are consistant withthe structure.

Analysis: Calc'd for C₁₃ H₁₁ N₃ O₅ S (321.30), C, 48.60; H, 3.45; N,13.08; S, 9.98. Found: C, 48.62; H, 3.61; N, 13.28; S, 10.19.

EXAMPLE 3 ##SPC12##

To 300 ml DMF is added 67.5 grams (1.25 moles) of sodium methoxide. Thisis heated to 55°C. whereupon a solution of 100 grams (0.31 moles) of2,3-dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide1,1-dioxide in 350 ml of DMF is added. The temperature is maintained at60°-70°C. for a half hour and poured into aqueous acid. This afforded 71grams (71%) of crude product V.

Purification is achieved by a hot aqueous methanol treatment, and thisafforded1-{[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanoneS,S-dioxide, mp 187°-189°C.; IR and NMR are consistant with thestructure.

Analysis: Calc'd for C₁₃ H₁₁ N₃ O₅ S (321.30), C, 48.60; H, 3.45; N,13.08; S, 9.98. Found: C, 48.55; H, 3.49; N, 12.93; S, 10.16.

EXAMPLE 4 ##SPC13##

To 160 ml of 56% aqueous proprietary solvent No. 3 (SOLOX) is added 3.21grams (0.01 mole) of1-{[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]-methyl}ethanoneS,S-dioxide and the mixture is cooled to 5°C., whereupon 20 ml of 1 NNaOH is added dropwise, the temperature being maintained below 10°C. Tothis is added 1.8 grams (0.015 mole) of dimethylsulfate and the reactionmixture is stirred for 3 hours, maximum temperature 25°C. Acidificationwith 6 N HCl afforded 2.8 grams (85%) of analytical1-{[5-(4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanoneS,S-dioxide, mp 143°C.-145°C.; IR and NMR are consistant with thestructure.

Analysis: Calc'd for C₁₄ H₁₃ N₃ O₅ S (335.32) C, 50.15; H, 3.91; N,12.53; S, 9.56. Found: C, 49.97; H, 3.98; N, 12.52; S, 9.72.

EXAMPLE 5 ##SPC14##

To 80 ml xylene is added 4.0 grams (0.012 mole) of1-{[5-(4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanoneS,S-dioxide followed by 0.4 grams (0.0046 mole) of triethylamine and thetemperature is brought to 115°-120°C. for 30 minutes. The reactionmixture is cooled and filtered to afford 3.6 grams (90%) of4-hydroxy-3-(5-methyl-3-isoxazolycarbomoyl)-2-methyl-2H-1,2-benzothiazine1,1-dioxide, mp 252°-254°C.

Analysis: Calc'd for C₁₄ H₁₃ N₃ O₅ S (335.32) C, 50.15; H, 3.91; N,12.53; S, 9.56. Found: C, 49.96; H, 3.95; N, 12.47; S, 9.58.

EXAMPLE 6 ##SPC15##

To 20 ml DMF is added 3.2 grams (10 mmol) of the unalkylated oxadiazole,1-{[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanoneS,S-dioxide. To this is added 0.9 grams of 57% NaH (21.4 mmol) and thetemperature rises to 60°C. The temperature is allowed to cool naturallyto 25°C., whereupon 1.4 grams (10 mmol) of methyl iodide dissolved in 1ml of DMF is added. The reaction is heated (60°C.) for 2 hours, cooledand acidified to give 2.3 grams (70%) of a material whose thin layerchromatography matched that of4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine1,1-dioxide of Example 5.

EXAMPLE 7 ##SPC16##

To 60 ml SOLOX is added 3.21 grams (0.01 mole) of1-{[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanoneS,S-dioxide followed by 35 ml of 1 N NaOH. To this is added 1.89 grams(0.015 mole) of dimethylsulfate and the reaction is heated to reflux(75°-80°C.) for one and a half hours. Cooling and filtration afforded2.3 grams (70%) of crude product I. Purification (DMF/SOLOXrecrystallization) gave4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine1,1-dioxide, mp 247°-250°C. dec. whose thin layer chromatography isidentical to the material prepared directly from1-{[5-(4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanoneS,S-dioxide in Example 5.

We claim:
 1. 3-(Chloroacetamido)-5-methylisoxazole.